Treatments Using Venlafaxine

ABSTRACT

This; invention provides a method of treating obesity, generalized anxiety disorder, post-traumatic stress disorder, late luteal phase dysphoric disorder (premenstrual, syndrome), attention deficit disorder, with and without hyperactivity, Gilles de la Tourette syndrome, bulimia nervosa or Shy Drager Syndrome in a: mammal by administering to the mammal an effective amount of a hydroxycycloalkanephenethyl amine of the following structural formula: 
     
       
         
         
             
             
         
       
     
     in which A is a moiety of the formula 
     
       
         
         
             
             
         
       
     
     where
         the dotted line represents optional unsaturation;   R 1  is hydrogen or alkyl;   R 2  is alkyl;   R 4  is hydrogen, alkyl, formyl, or alkanol;   R 5  and R 6  are, independently, hydrogen, hydroxyl, alkyl, alkoxy, alkanoyloxy, cyano, nitro, alkylmercapto, amino, alkylamino, dialkylamino, alkanamido, halo, trifluoromethyl, or taken together, methylene dioxy;   R 7  is hydrogen or alkyl; and   n is 0, 1, 2, 3, or 4;
 
or a pharmaceutically acceptable salt thereof:

BACKGROUND OF THE INVENTION

This is a continuation of copending application Ser. No. 10/721,629filed Aug. 2, 2005, which is a division of application Ser. No.10/396,043, filed on Mar. 25, 2003, which is a division of applicationSer. No. 09/996,590, filed on Nov. 30, 2001, now U.S. Pat. No.6,555,586, which is a division of application Ser. No. 09/892,363, filedon Jun. 27, 2001, now U.S. Pat. No. 6,465,524, which is a division ofapplication Ser. No. 09/769,998, filed on Jan. 25, 2001, now U.S. Pat.No. 6,444,708, which is a division of application Ser. No. 09/285,812,filed on Apr. 2, 1999, now U.S. Pat. No. 6,310,101, which is a divisionof application Ser. No. 08/835,780, filed on Apr. 8, 1997, now U.S. Pat.No. 5,916,923, which is a continuation of application Ser. No.08/368,521, filed on Jan. 4, 1995, now abandoned, which is acontinuation of application Ser. No. 08/083,848, filed, on Jun. 28,1993, now abandoned.

The active ingredients of this invention include(1-[2-(dimethylamino)-1-(4-methoxyphenyl) ethyl] cyclohexanol), ortherapeutically acceptable salts thereof, which are known generally asvenlafaxine and its analogues. Venlafaxine is disclosed in U.S. Pat. No.4,535,186 (Husbands et al.) and has been previously reported to beuseful as an antidepressant. U.S. Pat. No. 4,535,186 teaches theproduction of venlafaxine and its analogues and is incorporated hereinas reference. For the purposes of this disclosure, and the claims thatfollow, the use of venlafaxine is understood to include the free baseand pharmaceutically acceptable salt forms of venlafaxine, the racemateand its individual enantiomers, and venlafaxine analogs, both asracemates and as their individual enantiomers.

Venlafaxine has been shown to be a potent inhibitor of monoamineneurotransmitter uptake, a mechanism associated with clinical,antidepressant activity. Due to its hovel structure, venlafaxine has amechanism of action unrelated to other available antidepressants, suchas the tricyclic antidepressants desipramine, nostriptyline,protriptyline, imipramine, amitryptyline, trimipramine and doxepin.

It is believed that venlafaxine's mechanism of action, is related topotent inhibition of the uptake of the monoamine neurotransmittersserotonin and norepinephrine. To a lesser degree, venlafaxine alsoinhibits dopamine reuptake, but it has no inhibitory activity onmonoamine oxidase. O-desmethylvenlafaxine, venlafaxine's majormetabolite in humans, exhibits a similar pharmacologic profile.Venlafaxine's ability to inhibit norepinephrine and serotonin (5-HT)uptake has been predicted to have an efficacy which rivals or surpasesthat of tricyclic antidepressants (Stuart A. Montgomery, M. D., J. ClinPsychiatry, 54:3, March 1993).

In contrast to classical tricyclic antidepressant drugs, venlafaxine hasvirtually no affinity for muscarinic, histaminergic or adrenergicreceptors in vitro. Pharmacologic activity at these receptors isassociated with the various anticholinergic, sedative and cardiovasculareffects seen with the tricyclic; antidepressant drugs.

DESCRIPTION OF THE INVENTION

In accordance with the present invention there is provided a method oftreating, preventing, or controlling obesity, panic disorder,post-traumatic stress disorder, late luteal phase dysphoric disorder(premenstrual syndrome), attention deficit disorders, with and withouthyperactivity, Gilles de la Tourette syndrome, bulimia nervosa,generalized anxiety disorder or Shy Drager Syndrome in mammals-,preferably in humans. Each of these disorders exhibit a physiologicalbasis for treatment by venlafaxine's ability to inhibit monoamineneurotransmitters.

Bulimia Nervosa is characterized by recurrent binge eating in which theindividual feels a loss of control over eating and regularly practicesrigorous dieting or fasting, or purging by self-induced vomiting, or theuse of diuretics, or laxatives in an attempt to overcome the feeling.Eating binges are generally episodic and may be triggered bypsychosocial stress and may occur as often as several times a day. As anantidepressant, venlafaxine can be used to reduce the frequency ofbinging and purging in both and nondepressed bulimics.

Several links exist between late luteal phase dysphoric disorder (LLPDD)and major depression, including similar clinical features and anincreased lifetime prevalence of major depression in women with LLPPD.In addition, women with confirmed LLPDD have demonstrated abnormalitiesin premenstrual levels of serotonin. Premenstrual carbohydrate cravingand increased carbohydrate intake in patients with this condition arealso suggestive of serotonin involvement. Venlafaxine and its analoguesare effective in treating LLPDD because of their serotonin uptakeinhibitory ability.

Similarly, the antidepressant activity of venlafaxine and its analoguescan be used in the treatment of attention deficit disorders (ADD), withand without hyperactivity, which is characterized by strong behavioralabnormalities. ADD occurs in between 3 and 10% of school age childrenand is one of the most common childhood and adolescent psychiatricconditions. At the present time, there are three hypotheses suggestingthat deficits or dysregulation, of the monoamine neurotransmitter systemexists in ADD, specifically deficits in noradrenergic dopaminergic andserotonergic neuronal systems.

Psychopharmacological treatment has proven beneficial in many patientswith ADD. The psychotropics most commonly used have come from twodifferent medication groups, the psychostimulants and antidepressants.Imipramine and desipramine have been most commonly prescribed for thetreatment of ADD, though fluoxetine has also been used.

One related disorder of interest to the, present invention is Gilles dela Tourette syndrome, which is often referred to as Tourette syndrome orTourette's syndrome. The malady may begin with simple tics, but canprogress to multiple, complex movements, which may include vocal andrespiratory tics. The vocal tics associated with the syndrome mayinclude grunting or barking noises or may amount to compulsiveutterances, often including involuntary curses or derogatory remarks.Agents currently used in the treatment of Tourette syndrome includebenzodiazepine anxiolytics, such as lorazepam, for simple tics andhaloperidol, clonidine or pimozide for more advanced cases of thesyndrome.

Generalized Anxiety Disorder is a syndrome characterized by excessive orchronic anxiety or apprehension concerning two or more of life'scircumstances. The disorder's signs and symptoms often include somaticcomplaints, such as tremor, dyspnea, palpitations, lightheadedness, andnausea.

Acute anxiety attacks (panic disorders) are a defining symptom ofanxiety neurosis arid are extremely unpleasant for the patient whoexperiences a subjective fear which arises for no apparent reason. Thisfear may be a fear of some imminent catastrophe which prevents rationalreasoning.

Such anxiety disorders have been treated by a combination of psychologicand pharmocologic measures. Psychologic treatments may include insightpsychotherapy, supportive psychotherapy and relaxation techniques, suchas meditation or hypnosis. Pharmocologic treatments include thosemedications that lower the stress level of the patient. Minortranquilizers are used for controlling the symptoms of chronic oranticipatory anxiety. Panic attacks can be prevented or reduced inseverity by therapeutic doses of antidepressants, including venlafaxineand other serotonin reuptake inhibitors, tricyclic antidepressantmedications or monoamine oxidase inhibitors.

Venlafaxine and its analogues can also be used to treat Post TraumaticStress Disorder (PTSD), which may develop after exposure to severestresses, such as combat, accident, assaults and natural disasters. PTSDis characterized by symptoms of hyperalertness, sleep disturbance,survivor guilt, impairment of concentration and memory, avoidance ofreminders and recollection of traumatic events, intensive daydreams ofimages, and recurrent nightmares.

While treatment for PTSD consists largely of relaxation techniquesdesigned at relieving the hyperarousal and anxiety symptoms,antidepressants, including serotonin uptake inhibitors, assist inpatient recovery.

Venlafaxine and its analogues can also be used as a part of a medicalregimen associated with Shy-Drager Syndrome (SDS), which is a multiplesystems degeneration resulting in widespread neurologic damage.Autonomic dysfunction with cerebellar ataxia, parkinsonism,corticospinal and corticobulbar trost dysfunction, and amyotrophy areknown to occur. The cause of SDS is unknown and its course isprogressive. Severe disability or death usually occurs within five toten years after onset, often from bulbar dysfunction and/or laryngealstridor.

The methods of the present invention involve administering to a mammalin need thereof an effective amount of one or more compounds from agroup of substituted phenelhylamines. The compounds of this inventionpresent the following structural formula:

in which A is a moiety of the formula

where

the dotted line represents optional unsaturating;

R₁ is hydrogen or alkyl of 1 to 6 carbon atoms;

R₂ is alkyl of 1 to 6 carbon atoms;

R₄ is hydrogen, alkyl of 1 to 6 carbon atoms, formyl, or alkanol of 2 to7 carbon atoms;

R₅ and R₆ are independently hydrogen, hydroxyl, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 7 carbonatoms, cyano, nitro, alkylmercapto of 1 to 6 carbon atoms, amino,alkyl-amino of 1 to 6 carbon atoms, dialkylamino in which each alkylgroup is of 1 to 6 carbon atoms, alkanamido of 2 to 7 carbon atoms,halo, trifluoromethyl, or when taken together, methylene dioxy;

R₇ is hydrogen or alkyl of 1 to 6 carbon atoms; and n is one of theintegers 0, 1, 2, 3, or 4;

or a pharmaceutical acceptable salt thereof.

The preferred compounds are those of the formula:

in which

A is as defined supra;

R₁ is hydrogen or alkyl of 1 to 3 carbon atoms;

R₂ is alkyl of 1 to 3 carbon atoms;

R₅ is hydrogen, hydroxyl, alkoxy of 1 to 3 carbon atoms, chloro, bromo,trifluoromethyl or alkyl of 1 to 3 carbon atoms;

R₆ is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms,chloro, bromo, trifluoromethyl or alkanoyloxy of 2 to 3 carbon atoms;

R₇ is hydrogen or alkyl of 1 to 3 carbon atoms;

or a pharmaceutical acceptable salt thereof.

The most preferred compounds are those in which R₅ and R₆ are both inthe meta positions or one of R₅ or R₆ is in the para position and n is2.

Of particular interest are the compounds1-[(2-dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol and1-[(2-dimethylamino)-1-(4-hydoxyphenyl)ethyl]cyclohexanol and theenantiomers and pharmaceutically acceptable salts thereof.

The compounds in which R₄ is formyl or alkanoyl of 2 to 7 carbon atoms

have been found to be not as potent as the corresponding free hydroxybearing derivatives. However, in long term therapy the acyloxyderivatives will act as pro drugs as the acyl group is removed in vivoeither via acid hydrolysis in the stomach or enzymatically.

The pharmaceutically acceptable acid addition salts of the basiccompounds of this invention are formed conventionally by reaction of thefree base with ah equivalent amount of any acid which forms a non-toxicSalt. Illustrative acids are either inorganic or organic, includinghydrochloric, hydrobromic, fumaric, maleic, succinic, sulfuric,phosphoric, tartaric, acetic, citric, oxalic and similar acids. Forparenteral administration, the use of water soluble salts is preferred,although either the free base of the pharmaceutically acceptable saltsare applicable for oral or parenteral administration of theantidepressant agents of this invention. The halo substituentrepresenting R₅ or R₆ is intended to include the chloro, bromo, iodo orfluoro substituents,

Pharmaceutical compositions containing the compounds of this inventionrepresent an additional aspect of this invention, the active ingredientcan be compounded into any of the usual oral dosage forms includingtablets, capsules and liquid preparations such as elixirs andsuspensions containing various coloring, flavoring, stabilizing andflavor masking substances. For compounding oral dosage forms, the activeingredient can be mixed with various conventional tabletting materialssuch as starch, calcium carbonate, lactose, sucrose and dicalciumphosphate to aid the tabletting or capsulating process. Magnesiumstearate, as an additive, provides a useful lubricant function whendesired.

The active ingredients can be dissolved or suspended in a pharmaceuticalacceptable sterile liquid carrier, such as sterile water, sterileorganic solvent or a mixture of both. Preferably a liquid carrier is onesuitable for parenteral injection. Where the active ingredient issufficiently soluble it can be dissolved in normal saline as a carrier;if it is too insoluble for this it can often be dissolved in a suitableorganic solvent, for instance aqueous propylene glycol or polyethyleneglycol solutions. Aqueous propylene glycol containing from 10 to 75% ofthe glycol by weight is generally suitable. In other instances othercompositions can be made by dispersing the finely-divided activeingredient in aqueous starch or sodium carboxymethyl cellulose solution,or in a suitable oil, for instance arachis oil. Liquid pharmaceuticalcompositions which are sterile solutions or suspensions can be utilizedby intramuscular, intraperitoneal or subcutaneous injection.

Preferably the pharmaceutical composition is in unit dosage form, e.g.as tablets or capsules. In such form, the composition is sub-divided inunit doses containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged compositions, for example,packeted powders or vials or ampoules. The unit dosage form can be acapsule, cachet or tablet itself, or it can be the appropriate number ofany of these in package form. The quantity of the active ingredient in aunit dose of composition may be varied or adjusted from 2 mg or less to50 mg or more, according to the particular need and the activity of theactive ingredient. The usual oral recommended dose of venlafaxine forhumans may be between about 75 and about 200 mg/day and this dose may beadministered in two or three divided doses, preferably with food ifadministered orally. A maximum recommended daily dose for humans wouldbe about 375 mg, but it will be understood by one skilled in the artthat dosage under this invention will be determined by the particularcircumstances surrounding each case.

One skilled in this art will also be aware that the routes ofadministering the compounds of this invention may vary significantly, Inaddition to other oral administrations; sustained release compositionsmay be favored. Other acceptable routes may include, but are not limitedto, intravenous intramuscular and intraperitoneal injections, subdermalimplants, as well as buccal, sublingual, transdermal, topical, rectal,vaginal and intranasal administrations. Bioerodible, non-bioerodible,biodegradable and non-biodegradable systems of administration may alsobe used.

It should also be understood that the present invention is intended toinclude all methods of, and reasons for, treating obesity, panicdisorder, post-traumatic stress disorder, late luteal phase dysphoricdisorder (premenstrual syndrome), attention deficit disorders, with andwithout hyperactivity, Gilles de la Tourette syndrome, bulimia nervosa,generalized anxiety disorder or Shy Drager Syndrome in mammals,preferably in humans. For the purposes of this invention, treating thesemaladies and disorders is to be understood as including allprophylactic, therapeutic, progression inhibiting, remedial,maintenance, curative or other treatments, regimens or administrationsof or with venlafaxine that yield the desired effects in the mammalreceiving venlafaxine.

The following example is provided to demonstrate the use of venlafaxinein the treatment of obesity. This example is merely illustrative anddoes not limit the scope of the present invention.

Obesity Reduction Test

A randomized double-blind comparison of venlafaxine and placebo capsuleswas tested as a treatment for obesity in non-depressed outpatients. Thetest was conducted over a period of ten (10) weeks with 98 peoplebetween the ages of 18 and 65 receiving double-blind medication (50receiving venlafaxine and 48 receiving a placebo). Each participant inthe comparison weighed more than 20%, but less than 100%, above the meanvalue for sex, height and bone structure according to the 1983Metropolitan Height and Weight Table. The women in the comparison ofchildbearing potential received a negative pregnancy test result andagreed to use medically acceptable forms of contraception throughout theperiod covered by the comparison.

The initial venlafaxine dose was 25 mg at bedtime on study day 1.Subsequently the dose was increased from 50 mg/day to 150 mg/day throughstudy day 14. On study day 15 the dose was increased to 225 mg/day (3tablets 3 time a day) and this dose was continued for the remainder ofthe 70 day study. The patients in both groups were also giveninstructions to decrease their food intake by 20% and to increase theirexercise by the same amount. These directives were given to standardizedietary instructions and to try to prevent patients from staring “crash”diets or exercise programs. A specific diet was not prescribed.

Comparisons within groups were performed on changes from baseline weightand body mass index. Body mass index was computed according to thefollowing formula:

${{Body}\mspace{14mu} {Mass}\mspace{14mu} {Index}} = \frac{{Weight}\mspace{14mu} \left( {{lb}.} \right) \times 100}{{Height}\mspace{14mu} \left( {{in}.} \right) \times {Height}\mspace{14mu} \left( {{in}.} \right)}$

Obesity Reduction Test Results

The venlafaxine group showed consistent statistically significant meanweight decreases and mean percent decreases from baseline beginning atweek 1. Overall, the mean decrease in body weight for the venlafaxinegroup at week 10 was 7.5 lb with a mean percent decrease from baselineof 3.6%. In contrast, the mean decrease in body weight for the placebogroup at week 10 was 1.3 lb with a mean percent decrease from baselineof 0.7%. The body mass index evaluation for the venlafaxine also showeda pattern of decreases similar to that of the weight decreases.

1. A method of treating bulimia nervosa in a mammal, comprisingadministering to the mammal an effective amount of a compound of theformula:

in which A is a moiety of the formula

wherein the dotted line represents optional unsaturation; R₁ is hydrogenor alkyl of 1 to 6 carbon atoms; R₂ is alkyl of 1 to 6 carbon atoms; R₄is hydrogen, alkyl of 1 to 6 carbon atoms, formyl,, or alkanol of 2 to 7carbon atoms; R₅ and R₆ are, independently, hydrogen, hydroxyl, alkyl of1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to7 carbon atoms, cyano, nitro, alkylmercapto of 1 to 6 carbon atoms,amino, alkylamino of 1 to 6 carbon atoms, dialkylamino in which eachalkyl group is of 1 to 6 carbon atoms, alkanamido of 2 to 7 carbonatoms, halo, trifluoromethyl, or taken together, methylene dioxy; R₇ ishydrogen or alkyl of 1 to 6 carbon atoms; and n is 0, 1, 2, 3, or 4; ora pharmaceutical acceptable salt thereof.
 2. The method of claim 1wherein the mammal is a human.
 3. The method of claim 1 wherein thecomposition is administered orally.
 4. A method of treating bulimianervosa in a mammal, comprising administering to the mammal apharmaceutical composition comprising an effective amount of a compoundof the formula:

in which A is a moiety of the formula

wherein the dotted line represents optional unsaturation, and R₁ ishydrogen or alkyl of 1 to 6 carbon atoms; R₂ is alkyl of 1 to 6 carbonatoms; R₄ is hydrogen, alkyl oft to 6 carbon atoms, formyl, or alkanolof 2 to 7 carbon atoms; R₅ and R₆ are, independently, hydrogen,hydroxy), alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms,alkanoyloxy of 2 to 7 carbon atoms, cyano, nitro, alkylmercapto of 1 to6 carbon atoms, amino, alkylamino of 1 to 6 carbon atoms; dialkylaminoin which each alkyl group is of 1 to 6 carbon atoms, alkanamido of 2 to7 carbon atoms, halo, trifluoromethyl, or taken together, methylenedioxy; R₇ is hydrogen or alkyl of 1 to 6 carbon atoms; and n is 0, 1, 2,3, or 4; or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or excipient.
 5. The method of claim4 wherein the compound is:

in which A is a moiety of the formula

wherein the dotted line represents optional unsaturation and R₁ ishydrogen or alkyl of 1 to 3 carbon atoms; R₂ is alkyl of 1 to 3 carbonatoms; R₅ is hydrogen, hydroxyl, alkoxy of 1 to 3 carbon atoms, chloro,bromo, trifluoromethyl or alkyl of 1 to 3 carbonatoms; R₆ is alkyl of 1to 3 carbon atoms; alkoxy of 1 to 3 carbon atoms, chloro, bromo,trifluoromethyl or alkanoyloxy of 2 to 3 carbon atoms; R₇ is hydrogen oralkyl of 1 to 3 carbon atoms; or a pharmaceutically acceptable saltthereof.
 6. The method of claim 1 wherein R₅ and R₆ are both in the metapositions or one of R₅ or R₆ is in the para position and n is
 2. 7. Themethod of claim 1 wherein the compound is1-[(2-dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol or apharmaceutically acceptable salt thereof.
 8. The method of claim 1wherein the compound is1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol or apharmaceutically acceptable salt thereof.
 9. The method of claim 1wherein the effective amount comprises a daily dose of between about 50mg/day and about 375 mg/day.
 10. The method of claim 1 wherein theeffective amount comprises a daily dose of between about 75 mg/day andabout 200 mg/day.
 11. The method of claim 1 wherein the mammal is ahuman.
 12. The method of claim 1 wherein the pharmaceutical compositionis administered orally.
 13. The method of claim 1 wherein thepharmaceutical composition is in a unit dosage form which is a tablet.14. The method of claim 1 wherein the pharmaceutical composition is in aunit dosage form which is a capsule.